Novel Roflumilast analogs as soft PDE4 inhibitors

被引：32

作者：

Boland, Sandro ^{[1
]}

Alen, Jo ^{[1
]}

Bourin, Arnaud ^{[1
]}

Castermans, Karolien ^{[1
]}

Boumans, Nicki ^{[1
]}

Panitti, Laura ^{[1
]}

Vanormelingen, Jessica ^{[1
]}

Leysen, Dirk ^{[1
]}

Defert, Olivier ^{[1
]}

机构：

[1] Amakem NV, B-3590 Diepenbeek, Belgium

来源：

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS | 2014年 / 24卷 / 18期

关键词：

PDE4; inhibitors; Soft drug; SAR; Esterase; COPD; PHOSPHODIESTERASE-4; INHIBITORS; ASTHMA;

D O I：

10.1016/j.bmcl.2014.07.016

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

PDE4 inhibitors are of high interest for treatment of a wide range of inflammatory or autoimmune diseases. Their potential however has not yet been realized due to target-associated side effects, resulting in a low therapeutic window. We herein report the design, synthesis and evaluation of novel PDE4 inhibitors containing a gamma-lactone structure. Such molecules are designed to undergo metabolic inactivation when entering circulation, thereby limiting systemic exposure and reducing the risk for side effects. The resulting inhibitors were highly active on both PDE4B1 and PDE4D2 and underwent rapid degradation in human plasma by paraoxonase 1. In contrast, their metabolites displayed markedly reduced permeability and/or on-target activity. (C) 2014 Elsevier Ltd. All rights reserved.

引用

页码：4594 / 4597

页数：4

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